Separation of 4-(4&#39;-cyano-4&#39;, 4&#39;-diphenyl-butyl-2&#39;)-morpholine from its isomer



Patented May 16, 1950 SEPARATION OF 4 (4 CYANQ- ifl'li-DI- PHENYL BU'I YL 2'.) MORPHQLINE F O rrs ISOMER Evelyn H. Wilson, Newark, N. J., assignor to Merck '& 00., Ina, Rahway, J a -corporation of New Jersey No Drawing. Application June 11,,19d8,

Serial No. 32 ,'5.? ,1

9 Claims. (01 260-247.)

This invention is concerned with the separation of 4- (4'-cyano-4',4"'-'diphenyi butyl 2) morpholine fromits isomer 4-(-3-cyano-3,3-diphenyi 2' methyl propyl 1') morpholine.

(4-cyano 4Z4" diphe'nyl butyl 2) morpholine' is an important intermediate in the synthesis of- 4 ,4-dipheny16'- (4 morpholinyl) 'heptanone 3 hydrochloride. This latter compound has analgesicprop'erties and is useful as a morphine substitute.

' 4-(4' -fcya'no4=",4 diphenyl butyl 2) morpholine is ordinarily prepared by the condensation of 4 (2-c'h1 oropropyl) morpholine with "diphenylaeetonitrile utilizing the conventional "procedure for reacting N-s'ubstituted-(2'-chloropropyli' amines with di'phenylacetonitrile as described by Sohul tz' et all (J.-" Aj'C. S. 69, pages 1&3; 1659,2454" and2459) and described in detail in a tic-pending application of applicants assignee, Serial No. 791,655, filed December 13, 1947, now abandoned. This synthesisresults in the formation of two isomeric products owing to the two ways in which the intermediate ethyleneimm'o'm'um ring can open duringalkylation. This reaction may be chemically represented by the following equation:"

Breviously the desired 4,4-dipheny1-6-( y-mor- 'ph o linyl) -hepta'none'-3 hydrochloride has been prepared by treating this mixture of nit'riles with ethyl magnesiumbromide and then with hydro "ch loric acid. The separation of said 4,4 -diphenyl- 2 obtained previously in the one-step process where "mixture of 'nitriles was itself reacted with ethyl 'm'ag'nesium bromide. "Itisnowdiscovered that the mixture of the nitriles', 4-(dcyano-4,4 diphenylbutyl 2 rnorpholine and '4 (3 wand-"323' diphenyl- 2'-niethyl-propyl-l)'morpholine, can be separated 'f'romea'eh'other and the individual nitrile isomers recovered in' substantially pure form. This is' accomplished by converting the mixture (if Iiitiilg into their Salts a'hydiohalic acid or with a substituted benzene sulfonic acid; It is preferred'to employ salts'o'f an acid selected from "the class which consists of hydrochloric acid, hyd'robromie acid, 2,55dich1orobienzene-sul ionic acid, mnitroben'zlene'sulfohic' acid and p chloroben zenesulfonie acid,'fractionally crystallizi'n'g said mixture of salts toproduce' the correspondi'ngsalt of "the desired isomer and 'deconiposing said salt by treatment with a base to produce the corresponding nitrile isoiriei.

It has been foundthat'the salts of"4-(4'-cyano- 4' 4 diphenyl butyi-2')-morphoiine are, in'ge'ne'ral, more soiuble' organic solvents than the 25 corresponding salts of 4- (3 -"cyano'- 3Z3" 11 pholine. When this material was reacted with ethyl magnesium bromide, the overall yield ,for the two step process of yi-A-diphenyI-G-( i morpholinyl i heptanone-g based on the starting W was 9 ni les was me -im e e wa 55 iifli tie 4- (3Geyanp-S',3'-dipheny1-2'- methyl propyl l :moipholine 4 'ried Oiit inan alcoholic solventfsueh'asethanol.

h reasimbs t e; min s an h fl e .w ed-benz tesu en a brid a y nduct e d'in solution in aqueous aceticacid; altliou h ot er qli' s p 'e c i v i be utilized if desired. 'Instead of preparing the salts of the nitriles by reacting the mixture of nitriles with the de-' sired acid, the salts'fa'ii be prepared by'metathe'sis a ibi se l sedtgm: ro at e 3 the mixture of the nitrile acetates (in aqueous acetic acid) can be reacted with a salt of the substituted-benzenesulfonic acid, such as the sodium salt, whereby the corresponding substituted benzenesulfonate of the mixed nitriles precipitates as an oil.

The mixture of nitriles, prepared as described corresponding nitrile can be recovered from this salt, if desired, by treatment with an aqueous alkaline solution such as an aqueous solution of an alkali metal hydroxide.

The solution obtained after removal of the salt of 4-(3'-cyano-3,3 diphenyl 2' methyl-propyl-1')-morpholine is then evaporated to small :volume. The salt of 4-(4'-cyano-4',4'-diphenylbutyl-2') -morpholine can be crystallized from the resulting concentrated solution. It is ordinarily preferred, however, to treat the filtrate containing said salt with an aqueous alkaline solution such as an aqueous solution of sodium hydroxide thereby precipitating the desired 4-(4'-cyano- 4. ,4-diphenyl-butyl-2) -morpholine. This product can be recovered by filtration and purified by crystallization from an alcoholic solution such as methanol, ethanol, isopropanol, and the like, or a hydrocarbon solvent such as petroleum ether. Alternatively, the combined solutions (after removal of the salt of 4=-(3'-cyano-3,3'-diphenyl- 2'-methyl-propyl-1) -morpholine) can be treated with aqueous sodium hydroxide and the precipitated solid extracted with an organic solvent such as ether, ether-benzene, and the like. The extract is dried and evaporated to produce 4- (4.- cyano 4,4' diphenyl butyl 2) morpholine which is then purified substantially as described above. 7

It is a preferred feature of this invention that the hydrochlorides of the mixture of nitriles have been found to have reversed solubility characteristics of those possessed by the other salts tried, 1. e. that the hydrochloride of the desired 4-(4- cyano-l' ,4 -diphenyl-butyl-2') -morphcline is less soluble in alcohols than the hydrochloride of 4- (3'-cyano-3,3'-diphenyl-2' methyl-propyl-l') This makes it possible to separate morpholine. the desired nitrile directly from the reaction mixture instead of resorting to the indirect method described above which involves separating the unwanted nitrile from the mixture and recovering 4-(4'-cyano- 4',4 -diphenyl-butyl-2')-morpholine from the liquors.

This preferred method comprises treating the mixture of nitriles with aqueous hydrochloric acid and then crystallizing the resulting mixture of hydrochlorides from solution in a lower aliphatic alcohol such as ethanol, methanol and the like, whereby 4- (4'-cyano-4=,4-diphenyl butyl-2) morpholine hydrochloride crystallizes in a yield of about 80% of that present in the mixture. This salt can be converted to the free nitrile as in the case of the salts described above, by treatment with a solution of a base such as sodium hydroxide.

- If desired, the 4-(3-cyano-3,'3'-diphenyl-2'- methyl-propyl-l) morpholine can be recovered from the alcohol solution after the removal of the 4-(4'-cyano 4Z4 diphenyl-butyl-Z') -morpholine hydrochloride. This is ordinarily accomplished by evaporating said solution to dryness and treating the residual material with an aqueous alkali metal hydroxide solution. The solid nitrile which precipitates is extracted with a solvent such as benzene-ether, and is recovered by evaporating the extract to dryness.

It is possible, utilizing the hydrochlorides as described above, to separate the individual nitrile components in substantially pure form and in a combined yield of over 85% of the total nitriles in the original mixture.

The .followingexamples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given by way of illustration and not of limitation.

Example 1 35 gms. of a mixture of 4-(4-cyano-4',4-diphenyl-butyl-Z') -morpho1ine and 4-(3'cyano- 3',3'-diphenyl-2'-methyl propyl-1')-morpholine melting at 85-92 C. (which mixture of nitriles is obtained by condensing 4-(2'-chloro-propyl)- morpholine with diphenyl acetonitrile) was dissolved in 75 cc. of warm isopropanol. 48% aqueous hydrobromic acid was added to this solution until the pH of the solution was 2. The solution was evaporated in vacuo to dryness. The residual material was dissolved in 50 cc. of methanol, 10 cc. of ether was added and the resulting solution was chilled and the sides of the vessel scratched to induce crystallization. The resulting solution was chilled overnight in an ice box and the crystalline product recovered by filtration and dried (M. P. 233-242" 0.). This product was recrystallized from absolute ethanol to produce 10 g. of substantially pure 4-(3'-cyano-3,3'- diphenyl-2'-methyl propyl-l)-morpholine-hydrobromide; M. P. 248-250 C.

The combined filtrates were evaporated in vacuo to small volume and 30% aqueous sodium hydroxide solution was added. The precipitated solid was extracted with ether and the ether layer was washed with water and dried over anhydrous calcium sulfate (Drierite). The other solution was then filtered and evaporated and the residual product crystallized from petroleum ether (Skelly solve C) to produce 13 gms. of 4-(4-cyano-4,4'-

diphenyl-butyl-Z') -morpholine; M. P. l04-107 C.

Example 2 A mixture of nitriles, obtained by the condensation of 4-(2-chloro-propyl) -morpholine with diphenyl acetonitrile, was reacted with hydrochloric acid to produce a mixture of hydrochlorides (M. P. 173-198 C.). 10 gms. of this mixture of nitrile hydrochlorides was dissolved in 35 cc. of absolute ethanol, and the solution was clarified by filtration. This solution was then seeded with the hydrochloride of the lower-melting nitrile (which can be prepared from the material prepared as described in Example 1), and the solution was allowed to remain undisturbed overnight at room temperature, The crystalline product which precipitated was recovered by filtration and washed with 10 cc. of absolute ethanol. The product was further purified by crystallization from 25 cc. of absolute ethanol to produce 4.6 gms. of substantially pure 4-(4"-cya'no-4',4'-diphenyl butyl 2') morpholine hydrochloride; M. P. 231-235 C. dec.

The purified hydrochloride was dissolved in hot water, 30% aqueous sodium hydroxide was added and the'white solid which precipitated was ex tracted with; ether. The other layer washed with water. driedlover anhydrous calcium sulfate (djrieritel and the:- eth ereal solution evaporated ta amass to produce 4.0 ems: of c-(afl-cyanodfi -diplrenyli-butylfi -morplioline;. P. 105

ioceci. The combined alcoholic filtrates; were.v evaporated's'to dryness and: the: residual wasidissolved in. warm water. 30% aqueous. sodium hydroxide wasadded; to: this. solution and the solid material: precipitatedewas: extracted 1 with benzenejaeth'er. The: benzene-ether extract was washed; with water, dried oreir anhydrous; cal-- cium sulfate tDrierite): and the filtered solution was evaporatedto dryness.- The-residual. mate;- rial was slurried with methanol. and the slurry chilled. and filtered to. produce 3 gms. of? 44-3.- cyanoz-3lg3 -diphenyly-. 2; "-met ,l-propyl -l l-mor pholme;:.-M-;Pa131*1136C.

Elc'dbipl 3' 11d ems. of a. mixture or 4.-(4 '-cyano:-4';4-diphenyl-butyl-Qf'I-morpholine' and. 4st3 -oyand- 3',3' -diplienyl: 2. methyl propyl l) -mrpho.- line (M: P; otthe: mixturewas 85-92 Ci.) was dis:- solved in 45 cc. of 36 aceticacid' by warming on thessteam bath. 8:4 gm'saof'sodium 2g5-dichlorobenzenesulfonate. in. 7.5 cc; or warm. water was addedlto: thisrsolutiorr. followed by r00 cc. of cold water; The mixture wasrchilled 'inran. ice bath whereupon an oil separated. The-aqueous layer was decanted and the oil was slurried with water until the-scenes; werea 'neutral to litmus. The excess water was drained and :30 cc. of absolute alcohol was added. When all'of the oil had dissolved, a crystalline solid beganto separate. The mixture was allowed to remain at temperature for 2 hours, and the precipitated solid was recovered fromthe mixture by filtration and washedwith 10 cc. of. absolute ethanol. This icrudeproduct, which weighed.5..5 g ns. and melted at 212220 C., was recrystallized from methanol to produce the 2;5 dichlorobenzenesulfonic acid salt of4-(3- 'cyano=3-,3' diphenyl- 2"- methylpropyl- 1')-morpholine' in substantially pure" The ethanolic filtratewas evaporated in vacuo to a small volume and 30% aqueous sodium hydroxide solution was added. The solid was extracted from this mixture employing ether-benzene as the extraction solvent and the extract was washed with water and dried over anhydrous calcium sulfate (Drierite). The dried extract was then filtered and evaporated to dryness'and the residual material slurried with petroleum ether. The crystalline solid thus produced was recovered by filtration and dried to produce 5.5 gms. of crude material; M. P. 95-102 C. This product was recrystallized from ethanol to produce substantially pure 4- (4' cyano 4',4' diphenyl-butyl-Z')-morpholine; M. P. 105-107 C.

Example 4 10 gms. of mixed nitriles (M. P. 85-92 C. identical with the starting material employed in Example 3) was dissolved in 50 cc. of 36% acetic acid by warming on the steam bath. A solution of '7 gms. of p-chlorobenzenesulfonic acid monohydrate in 25 cc. of 36% acetic acid and cc. of water was added to the solution of the nitriles. 70 cc. of cold water was then added and the mixture was cooled to room temperature whereupon an oil separated. The aqueous layer was decanted and 25 cc. of 36% acetic acid was added added to the solution of the nitriles.

rated. was recoyerexr by-filtratibnand. washedwith water; This product; was recrystallized; irom ethanol to. produce; 3 ems.v or the. pr-chlorobenr zenesulfonic acid; salt: of 'l.-=3. *-0ilanQ3.'.3.-d1r phenyl-2f-methyl-propyl- Hi-morpholine in substantially pure form; M. P. 216-219 C.

The acetic acidfiltrata. upon: standin d positedan oil which slow-1y; crystallized. This material was filtered and recrystallized; from iso- -pro'p'anol; toproduce 3..51 0f. the phlorothe washes: were: neutral to litmus and the water was drained therefrom. 25 cc. ofabsolute ethanol wasv added, the solution. the beaker was scratched. to: induce crystallization and the solution was allowed toremain atroom temperature. overnight. The solid which separated Wasfilteredandi-washedwith 10 cc-. of absolute alcohol to produce. 417i gmsa. of the: m-nitrobem zenesulphonic acid salt of 4-(3-cyande3",3'-di The filtrate was evaporated. to small volume and 30% aqueous-sodium hydroxide. solution was added. The: solid which precipitated, was ex:- tracted with ether and the: ethereal extract. separated andwaslied with water'and' dried over anhydrouscalcium-sulfate (-Dr'ierite) The. solution was then filtered and evaporated. to dryness to produce 4 'gms. of" crude product; M. B. 92-97 C. This material was recrystallized? twice: from methanol to produce substantially puree-(4"- cyariot l"-dipl'ienyl-butyi 2-) morpholine; M. P. iQS-BG I 'C.

Various changes? and modifications' may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the annexed claims, they are to be considered as part of my invention.

I claim:

1. The process of recovering 4- (4-cyano-4,4'- diphenyl-butyl-Z)-morpholine from a mixture containing that compound and its isomer, 4-(3'- cyano 3,3' diphenyl 2 methyl-propyl-1')- morpholine, which comprises forming a mixture of salts of said isomers with an acid selected from the class which consists of hydrochloric acid, hydrobromic acid, 2,5-dichlorobenzenesulfonic acid, m-nitrobenzenesulfonic acid and p-chlorobenzenesulfonic acid, fractionally crystallizing said mixture of salts of said isomers with said acid thereby separating the corresponding salt of the desired isomer from said mixture and decomposing said salt by treatment with an aqueous alkaline solution to obtain said 4-(4'-cyano-4,4- diphenyl-butyl-2') -morpholine.

2. The process of recovering 4-(4-cyano- 4',4'-diphenyl-butyl-2') morpholine from a mixture containing that compound and its isomer 4 (3 cyano-3,3'-diphenyl-2'-methyl-propyl- 1') -morpholine, which comprises forming a mixto the oil. The crystallized solid which sepa- '15 ture of the hydrochloric acid salts of said isomers, fractionally 'crystallizing said mixture of hydroohlorides to produce the hydrochloride of the desired isomer and decomposing said hydrochloride by treatment with an aqueous alkaline solution to obtain said 4-(4'-cyano-4',4'-diphenyl-butyl-2) -morpholine.

3. The process which comprises preparing an alcoholic solution containing mixture of the hydrochlorides of 4-(4-cyano-4,4-diphenylbutyl-Z) -morpholine. and 4- (3'-cyano-3',3-diphenyl 2' methyl-propyl-l) -morpholine and crystallizing the sparingly-soluble hydrochloride of 4 (4-cyano-4',4'-diphenyl-butyl-2)-morpholine from said alcoholic solution.

4. The process which comprises preparing an ethanolic solution containing a mixture of the hydrochlorides of 4-(4'-cyano-4',4'-diphenylbutyl-Z) -morpholine and 4-(3'-cyano-3',3-diphenyl 2 methyl-propyl-l)-morpholine and crystallizing the sparingly-soluble hydrochloride of 4 (4' cyano-4',4'-diphenyl-butyl-2)-mor pholine from said ethanolic solution.

5. The process which comprises preparing an alcoholic solution containing a mixture of the hydrobromides .of 4-(4'-cyano-4',4'-diphenylbutyl-2')morpholine and 4-(3'-cyano-3,3-dipheny1-2 -methyl-propyl-1) -morpholine, crystallizing and filtering the sparingly-soluble hydrobromide of 4 (3' cyano-3,3'-diphenyl-2'- methyl-propyl-i')-morpholine from said alco-- holic solution, and recovering 4- (4-cyano-4',4- diphenyl-butyl-Z)-morpholine from the resulting solution.

6. The process which comprises preparing an isopropanol solution containing a mixture of the hydrobromides of 4-(4'-cyano-4,4'-diphenylbutyl-2)-morpholine and 4-(3-cyano-3',3-diphenyl-2-methyl-propyl-1')-morpholine, crystallizing and filtering the sparingly-soluble hydrobromide of 4 (3 cyano,-3,3'-diphenyl-2- methyl-propyl-l)-morpholine from said isopropanol solution, and recovering 4-(4-cyano- .4',4-diphenyl-butyl-2) -,morpholine from the resulting solution. I

'7. The process which comprises preparing an alcoholic solution containing a mixture of the 2,5-dichlorobenzenesulfonic acid salts of 4-(4- cyano-4L4-diphenyl-louty1-2)-morpholine and 4 (3' cyano-3',3'-diphenyl-2-methyl-propyll')-morpholine, crystallizing and filtering the sparingly-soluble 2,5 dichlorobenzenesulfonic acid salt of 4 (3 cyano 3,3-diphenyl-2'- methyl-propyl-l)-morpholine from said alcoholic solution, and recovering 4-(4'-cyano-4,4- diphenyl-butyl-z)-morpholine from the result.- ing solution.

8. The process which comprises preparing an alcoholic solution containing a mixture of the m-nitrobenzenesulfonic acid salts of 4-(4'- cyano-4',4 diphenyl-butyl-Z') -morpholine and 4 (3' cyano-3',3-dipheny1-2-methyl-propy1- 1')-morpholine, crystallizing and filtering the sparingly-soluble m-nitrobenzenesulfonic acid salt of 4 (3. cyano-3,3-diphenyl-2'-methylpropyl-1')-morpholine from said alcoholic solution, and recovering 4-(4'-cyano-4,4-diphenylbutyl-2')-morpholine from the resulting solution.

9. The process which comprises preparing an aqueous acetic acid solution containing a mixture of the p-chlorobenzenesulfonic acid salts of 4 (4' cyano 4',4 diphenyl-butyl-2)-morpholine, crystallizing and filtering the sparinglysoluble p-chlorobenzenesulfonic acid salt of 4- (3' cyano-3',3-dipheny1-2-methyl-propyl-1)- morpholine from said aqueous acetic acid solution, and recovering 4-(4-cyano-4,4-diphenylbutyl-2')-morpholine from the resulting solution;

EVELYN H. WILSON.

REFERENCES CITED The following references are of record in the file of this patent:

FOREIGN PATENTS Country Date Denmark Oct. 25, 1943 Number 

1. THE PROCESS OF RECOVERING 4-(4''-CYANO-4'',4''DIPHENYL-BUTYL-2'')-MORPHOLINE FROM A MIXTURE CONTAINING THAT COMPOUND AND ITS ISOMER, 4-(3''DYANO-3'',3'' - DIPHENYL - 2'' - METHYL-PROPYL-1'')MORPHOLINE, WHICH COMPRISES FORMING A MIXTURE OF SALTS OF SAID ISOMERS WITH AN ACID SELECTED FROM THE CLASS WHICH CONSISTS OF HYDROCHLORIC ACID, HYDROBROMIC ACID, 2,5-DICHLOROBENZENESULFONIC ACID, M-NITROBVENZENESULFONIC ACID AND P-CHLOROBENZENESULFONIC ACID, FRACTIONALLY CRYSTALLIZING SAID MIXTURE OF SALTS OF SAID ISOMERS WITH SAID ACID THEREBY SEPARATING THE CORRESPONDING SALT OF THE DESIRED ISOMER FROM SAID MIXTURE AND DECOMPOSING SAID SALT BY TREATMENT WITH AN AQUEOUS ALKALINE SOLUTION TO OBTAIN SAID 4-(4''-CYANO-4'', 4''DIPHENYL-BUTYL-2'')-MORPHOLINE. 